Mapping cortical change in Alzheimer's disease, brain development, and schizophrenia

This paper describes algorithms that can identify patterns of brain structure and function associated with Alzheimer's disease, schizophrenia, normal aging, and abnormal brain development based on imaging data collected in large human populations. Extraordinary information can be discovered with these techniques: dynamic brain maps reveal how the brain grows in childhood, how it changes in disease, and how it responds to medication. Genetic brain maps can reveal genetic influences on brain structure, shedding light on the nature-nurture debate, and the mechanisms underlying inherited neurobehavioral disorders. Recently, we created time-lapse movies of brain structure for a variety of diseases. These identify complex, shifting patterns of brain structural deficits, revealing where, and at what rate, the path of brain deterioration in illness deviates from normal. Statistical criteria can then identify situations in which these changes are abnormally accelerated, or when medication or other interventions slow them. In this paper, we focus on describing our approaches to map structural changes in the cortex. These methods have already been used to reveal the profile of brain anomalies in studies of dementia, epilepsy, depression, childhood- and adult-onset schizophrenia, bipolar disorder, attention-deficit/hyperactivity disorder, fetal alcohol syndrome, Tourette syndrome, Williams syndrome, and in methamphetamine abusers. Specifically, we describe an image analysis pipeline known as cortical pattern matching that helps compare and pool cortical data over time and across subjects. Statistics are then defined to identify brain structural differences between groups, including localized alterations in cortical thickness, gray matter density (GMD), and asymmetries in cortical organization. Subtle features, not seen in individual brain scans, often emerge when population-based brain data are averaged in this way. Illustrative examples are presented to show the profound effects of development and various diseases on the human cortex. Dynamically spreading waves of gray matter loss are tracked in dementia and schizophrenia, and these sequences are related to normally occurring changes in healthy subjects of various ages.

Procedural pain and brain development in premature newborns

Objective: Preterm infants are exposed to multiple painful procedures in the neonatal intensive care unit (NICU) during a period of rapid brain development. Our aim was to examine relationships between procedural pain in the NICU and early brain development in very preterm infants.

Methods: Infants born very preterm (N ¼ 86; 24–32 weeks gestational age) were followed prospectively from birth, and studied with magnetic resonance imaging, 3-dimensional magnetic resonance spectroscopic imaging, and diffusion tensor imaging: scan 1 early in life (median, 32.1 weeks) and scan 2 at term-equivalent age (median, 40 weeks). We calculated N-acetylaspartate to choline ratios (NAA/choline), lactate to choline ratios, average diffusivity, and white matter fractional anisotropy (FA) from up to 7 white and 4 subcortical gray matter regions of interest. Procedural pain was quantified as the number of skin-breaking events from birth to term or scan 2. Data were
analyzed using generalized estimating equation modeling adjusting for clinical confounders such as illness severity, morphine exposure, brain injury, and surgery.

Results: After comprehensively adjusting for multiple clinical factors, greater neonatal procedural pain was associated with reduced white matter FA (b ¼ 0.0002, p ¼ 0.028) and reduced subcortical gray matter NAA/choline (b ¼ 0.0006, p ¼ 0.004). Reduced FA was predicted by early pain (before scan 1), whereas lower NAA/choline was predicted by pain exposure throughout the neonatal course, suggesting a primary and early effect on subcortical structures with secondary white matter changes.

Interpretation: Early procedural pain in very preterm infants may contribute to impaired brain development.

Linking melanism to brain development: expression of a melanism-related gene in barn owl feather follicles covaries with sleep ontogeny.

BACKGROUND: Intra-specific variation in melanocyte pigmentation, common in the animal kingdom, has caught the eye of naturalists and biologists for centuries. In vertebrates, dark, eumelanin pigmentation is often genetically determined and associated with various behavioral and physiological traits, suggesting that the genes involved in melanism have far reaching pleiotropic effects. The mechanisms linking these traits remain poorly understood, and the potential involvement of developmental processes occurring in the brain early in life has not been investigated. We examined the ontogeny of rapid eye movement (REM) sleep, a state involved in brain development, in a wild population of barn owls (Tyto alba) exhibiting inter-individual variation in melanism and covarying traits. In addition to sleep, we measured melanistic feather spots and the expression of a gene in the feather follicles implicated in melanism (PCSK2). RESULTS: As in mammals, REM sleep declined with age across a period of brain development in owlets. In addition, inter-individual variation in REM sleep around this developmental trajectory was predicted by variation in PCSK2 expression in the feather follicles, with individuals expressing higher levels exhibiting a more precocial pattern characterized by less REM sleep. Finally, PCSK2 expression was positively correlated with feather spotting. CONCLUSIONS: We demonstrate that the pace of brain development, as reflected in age-related changes in REM sleep, covaries with the peripheral activation of the melanocortin system. Given its role in brain development, variation in nestling REM sleep may lead to variation in adult brain organization, and thereby contribute to the behavioral and physiological differences observed between adults expressing different degrees of melanism.

Early adversity, brain development and emotion processing in monozygotic twins

Il existe actuellement de nombreuses preuves démontrant que des facteurs génétiques et environnementaux interagissent pendant des périodes spécifiques du développement pour rendre une personne vulnérable aux troubles psychologiques via diverses adaptations physiologiques. Cette thèse porte sur l'impact de l’adversité prénatale (représentée par le petit poids à la naissance, PPN) et de l’adversité postnatale précoce (symptômes dépressifs maternels et comportements maternels négatifs), sur le développement du cerveau, particulièrement les régions fronto-limbiques impliquées dans le traitement des émotions, pendant l'enfance et l'adolescence. Des jumeaux monozygotes (MZ) sont utilisés, lorsque possible, afin de contrôler pour les effets génétiques. Les chapitres 1 et 2 présentent les résultats de la vérification de l'hypothèse que l’adversité prénatale et postnatale précoce sont associées à une altération du fonctionnement des régions fronto-limbique tels que l’amygdale, l’hippocampe, l’insula, le cortex cingulaire antérieur et le cortex préfrontal, en réponse à des stimuli émotifs chez des enfants et des adolescents. On observe que les symptômes dépressifs maternels sont associés à une activation plus élevée des régions fronto-limbiques des enfants en réponse à la tristesse. Les résultats de l’étude avec des adolescents suggèrent que le PPN, les symptômes dépressifs et les comportements maternels négatifs sont associés à une fonction altérée des régions fronto-limbiques en réponse à des stimuli émotionnels. Chez les jumeaux MZ on observe également que la discordance intra-paire de PPN et de certains comportements maternels est associée à une discordance intra-paire du fonctionnement du cerveau et que ces altérations diffèrent selon le sexe. Le chapitre 3 présente les résultats de la vérification de l'hypothèse que l’adversité prénatale et postnatale précoce sont associées à un volume total réduit du cerveau et de l’hypothèse que les comportements maternels peuvent servir de médiateur ou de modérateur de l'association entre le PPN et le volume du cerveau. Avec des jumeaux MZ à l’adolescence on observe a) que le PPN est effectivement associé à une diminution du volume total du cerveau et b) que la discordance intra-paire de PPN est associée à une discordance du volume du cerveau. En somme, cette thèse présente un ensemble de résultats qui soutiennent deux hypothèses importantes pour comprendre les effets de l’environnement sur le développement du cerveau : que l’environnement prénatal et postnatal précoce ont un impact sur le développement du cerveau indépendamment du code génétique et que les mécanismes impliqués peuvent différer entre les garçons et les filles. Finalement, l’ensemble de ces résultats sont discutés à la lumière des autres travaux de recherche dans ce domaine et des avenues à explorer pour de la recherche ultérieure sont proposées.

World Hunger, Malnutrition and Brain Development of Children

Hunger is still a major problem faced by people in the world especially in some areas in developing countries, and this condition is a cause of undernutrition. Insufficient nutrition during the early stages of life may adversely influence brain development. It was observed from my own research conducted in Bogor, Indonesia, that children with severe acute malnutrition (SAM, body mass index or BMI for age z score < -3) (N=54) had significantly (p<0.05) lower memory ability score (46.22±1.38) compared to normal children (BMI for age z score -2 ≤ z ≤ 1) (N=91) (51.56±1.24). Further, children with Moderate Acute Malnutrition (MAM, BMI for age z score -3 ≤ z <-2) tended to (p<0.1) have lower memory ability (50.08±1.58) than the normal children. On the other hand, overnutrition among children also might impair the brain function. The study revealed that children who are overweight (BMI for age z score 1 < z ≤ 2) (N=8) significantly (p<0.05) had lower memory ability score (46.13±4.50) compared to the normal children. This study also revealed that obese children (BMI for age z score > 2) (N=6) tended to (p<0.1) have lower memory ability score (50.33±5.64) than the normal children. It is therefore very important to maintain children at a normal BMI, not being undernourished (SAM and MAM categories) on one side and not being overnourished (overweight and obesity categories) on the other side in order to optimise their brain development. This could be achieved through providing children with an adequate and balanced nutrient supply via food.

Double burden malnutrition of preschool children and its association with brain development and milk consumption

Protecting the quality of children growth and development becomes a supreme qualification for the betterment of a nation. Double burden child malnutrition is emerging worldwide which might have a strong influence to the quality of child brain development and could not be paid-off on later life. Milk places a notable portion during the infancy and childhood. Thus, the deep insight on milk consumption pattern might explain the phenomenon of double burden child malnutrition correlated to the cognitive impairments. Objective: Current study is intended (1) to examine the current face of Indonesian double burden child malnutrition: a case study in Bogor, West Java, Indonesia, (2) to investigate the association of this phenomenon with child brain development, and (3) to examine the contribution of socioeconomic status and milk consumption on this phenomenon so that able to formulate some possible solutions to encounter this problem. Design: A cross-sectional study using a structured coded questionnaire was conducted among 387 children age 5-6 years old and their parents from 8 areas in Bogor, West-Java, Indonesia on November 2012 to December 2013, to record some socioeconomic status, anthropometric measurements, and history of breast feeding. Diet and probability of milk intake was assessed by two 24 h dietary recalls and food frequency questionnaire (FFQ). Usual daily milk intake was calculated using Multiple Source Method (MSM). Some brain development indicators (IQ, EQ, learning, and memory ability) using Projective Multi-phase Orientation method was also executed to learn the correlation between double burden child malnutrition and some brain development indicator. Results and conclusions: A small picture of child double burden malnutrition is shown in Bogor, West Java, Indonesia, where prevalence of Severe Acute Malnutrition (SAM) is 27.1%, Moderate Acute Malnutrition (MAM) is 24.9%, and overnutrition is 7.7%. This phenomenon proves to impair the child brain development. The malnourished children, both under- and over- nourished children have significantly (P-value<0.05) lower memory ability compared to the normal children (memory score, N; SAM = 45.2, 60; MAM = 48.5, 61; overweight = 48.4, 43; obesity = 47.9, 60; normal = 52.4, 163). The plausible reasons behind these evidences are the lack of nutrient intake during the sprout growth period on undernourished children or increasing adiposity on overnourished children might influence the growth of hippocampus area which responsible to the memory ability. Either undernutrition or overnutrition, the preventive action on this problem is preferable to avoid ongoing cognitive performance loss of the next generation. Some possible solutions for this phenomenon are promoting breast feeding initiation and exclusive breast feeding practices for infants, supporting the consumption of a normal portion of milk (250 to 500 ml per day) for children, and breaking the chain of poverty by socioeconomic improvement. And, the national food security becomes the fundamental point for the betterment of the next. In the global context, the causes of under- and over- nutrition have to be opposed through integrated and systemic approaches for a better quality of the next generation of human beings.

Upregulation of E2F1 in cerebellar neuroprogenitor cells and cell cycle arrest during postnatal brain development

In the developing cerebellum, proliferation of granular neuroprogenitor (GNP) cells lasts until the early postnatal stages when terminal maturation of the cerebellar cortex occurs. GNPs are considered cell targets for neoplastic transformation, and disturbances in cerebellar GNP cell proliferation may contribute to the development of pediatric medulloblastoma. At the molecular level, proliferation of GNPs is regulated through an orchestrated action of the SHH, NOTCH, and WNT pathways, but the underlying mechanisms still need to be dissected. Here, we report that expression of the E2F1 transcription factor in rat GNPs is inversely correlated with cell proliferation rate during postnatal development, as opposed to its traditional SHH-dependent induction of cell cycle. Proliferation of GNPs peaked at postnatal day 3 (P3), with a subsequent continuing decrease in proliferation rates occurring until P12. Such gradual decline in proliferating neuroprogenitors paralleled the extent of cerebellum maturation confirmed by histological analysis with cresyl violet staining and temporal expression profiling of SHH, NOTCH2, and WNT4 genes. A time course analysis of E2F1 expression in GNPs revealed significantly increased levels at P12, correlating with decreased cell proliferation. Expression of the cell cycle inhibitor p18 (Ink4c) , a target of E2F1, was also significantly higher at P12. Conversely, increased E2F1 expression did not correlate with either SMAC/DIABLO and BCL2 expression profiles or apoptosis of cerebellar cells. Altogether, these results suggest that E2F1 may also be involved in the inhibition of GNP proliferation during rat postnatal development despite its conventional mitogenic effects.

Expression Profile and Distribution of Efhc1 Gene Transcript During Rodent Brain Development

One of the putative causative genes for juvenile myoclonic epilepsy (JME) is EFHC1. We report here the expression profile and distribution of Efhc1 messenger RNA (mRNA) during mouse and rat brain development. Real-time polymerase chain reaction revealed that there is no difference in the expression of Efhc1 mRNA between right and left hemispheres in both species. In addition, the highest levels of Efhc1 mRNA were found at intra-uterine stages in mouse and in adulthood in rat. In common, there was a progressive decrease in Efhc1 expression from 1-day-old neonates to 14-day-old animals in both species. In situ hybridization studies showed that rat and mouse Efhc1 mRNAs are expressed in ependymal cells of ventricle walls. Our findings suggest that Efhc1 expression is more important during initial phases of brain development and that at this stage it could be involved in key developmental mechanisms underlying JME.

The brain in the jar : troubling the truths of discourses of adolescent brain development

Ideas about adolescent brains and their development increasingly function as powerful truths in making sense of young people. And it is the knowledge practices of the neurosciences and evolutionary and developmental psychology that are deemed capable of producing what we have come to understand as the evidence on which policy, interventions and education should be built. In effect these discourses reduce young people to little more than a brain in a jar. The paper examines how the evidence about adolescent brains - their volume, and the functioning and activity of different regions - from neuroscience and evolutionary and developmental psychology works as truth. What knowledge practices are used to produce this evidence, or are deemed capable of producing this evidence? What truth claims are able to attach to this evidence? What makes it true and why is it imagined as evidence of something that is true in policy, public and other research settings that are often far removed from where it was produced? I argue that the discourses of adolescent brain development disembody, reduce and simplify the complexities of these figures we know as adolescents. In effect they render the adolescent as a brain in a jar.

Effect of loss of CDKL5 on brain development in a new Cdkl5 knockout mouse model

Rett's Syndrome (RTT) is a severe neurodevelopmental disorder, characterized by cognitive disability that appears in the first months/years of life. Recently, mutations in the X-linked cyclin-dependent kinase-like 5 (CDKL5) gene have been detected in RTT patients characterized by early-onset seizures. CDKL5 is highly expressed in the brain starting from early postnatal stages to adulthood, suggesting the importance of this kinase for proper brain maturation and function. However, the role/s of CDKL5 in brain development and the molecular mechanisms whereby CDKL5 exerts its effects are still largely unknown. In order to characterize the role of CDKL5 on brain development, we created a mice carrying a targeted conditional knockout allele of Cdkl5. A first behavioral characterization shows that Cdkl5 knockout mice recapitulate several features that mimic the clinical features described in CDKL5 patients and are a useful tool to investigate phenotypic and functional aspects of Cdkl5 loss. We used the Cdkl5 knockout mouse model to dissect the role of CDKL5 on hippocampal development and to establish the mechanism/s underlying its actions. We found that Cdkl5 knockout mice showed increased precursor cell proliferation in the hippocampal dentate gyrus. Interestingly, this region was also characterized by an increased rate of apoptotic cell death that caused a reduction in the final neuron number in spite of the proliferation increase. Moreover, loss of Cdkl5 led to decreased dendritic development of new generated granule cells. Finally, we identified the Akt/GSK3-beta signaling as a target of Cdkl5 in the regulation of neuronal precursor proliferation, survival and maturation. Overall our findings highlight a critical role of CDKL5/AKT/GSK3-beta signaling in the control of neuron proliferation, survival and differentiation and suggest that CDKL5-related alterations of these processes during brain development underlie the neurological symptoms of the CDKL5 variant of RTT.